Molecular recognition of S-nitrosothiol substrate by its cognate protein denitrosylase.


Journal Article

Protein S-nitrosylation mediates a large part of nitric oxide's influence on cellular function by providing a fundamental mechanism to control protein function across different species and cell types. At steady state, cellular S-nitrosylation reflects dynamic equilibria between S-nitrosothiols (SNOs) in proteins and small molecules (low-molecular-weight SNOs) whose levels are regulated by dedicated S-nitrosylases and denitrosylases. S-Nitroso-CoA (SNO-CoA) and its cognate denitrosylases, SNO-CoA reductases (SCoRs), are newly identified determinants of protein S-nitrosylation in both yeast and mammals. Because SNO-CoA is a minority species among potentially thousands of cellular SNOs, SCoRs must preferentially recognize this SNO substrate. However, little is known about the molecular mechanism by which cellular SNOs are recognized by their cognate enzymes. Using mammalian cells, molecular modeling, substrate-capture assays, and mutagenic analyses, we identified a single conserved surface Lys (Lys-127) residue as well as active-site interactions of the SNO group that mediate recognition of SNO-CoA by SCoR. Comparing SCoRK127Aversus SCoRWT HEK293 cells, we identified a SNO-CoA-dependent nitrosoproteome, including numerous metabolic protein substrates. Finally, we discovered that the SNO-CoA/SCoR system has a role in mitochondrial metabolism. Collectively, our findings provide molecular insights into the basis of specificity in SNO-CoA-mediated metabolic signaling and suggest a role for SCoR-regulated S-nitrosylation in multiple metabolic processes.

Full Text

Duke Authors

Cited Authors

  • Stomberski, CT; Zhou, H-L; Wang, L; van den Akker, F; Stamler, JS

Published Date

  • February 1, 2019

Published In

Volume / Issue

  • 294 / 5

Start / End Page

  • 1568 - 1578

PubMed ID

  • 30538128

Pubmed Central ID

  • 30538128

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.RA118.004947


  • eng

Conference Location

  • United States